Expansion of G4C2 repeats within the C9ORF72 gene is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Such repeats lead to decreased expression of the autophagy regulator C9ORF72 protein. Furthermore, sense and antisense repeats are translated into toxic dipeptide repeat (DPR) proteins. It is unclear how these repeats are translated, and in which way their translation and the reduced expression of C9ORF72 modulate repeat toxicity. Here, we found that sense and antisense repeats are translated upon initiation at canonical AUG or near-cognate start codons, resulting in polyGA-, polyPG-, and to a lesser degree polyGR-DPR proteins. However, accumulation of these proteins is prevented by autophagy. Importantly, reduced C9ORF72 levels lead to suboptimal autophagy, thereby impairing clearance of DPR proteins and causing their toxic accumulation, ultimately resulting in neuronal cell death. Of clinical importance, pharmacological compounds activating autophagy can prevent neuronal cell death caused by DPR proteins accumulation. These results suggest the existence of a double-hit pathogenic mechanism in ALS/FTD, whereby reduced expression of C9ORF72 synergizes with DPR protein accumulation and toxicity.

中文翻译：

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C9ORF72丢失时自噬的减少与G4C2重复扩增疾病中的二肽重复蛋白毒性协同作用。

C9ORF72基因内G4C2重复序列的扩增是肌萎缩性侧索硬化症（ALS）和额颞痴呆（FTD）的最常见原因。这样的重复导致自噬调节剂C9ORF72蛋白的表达降低。此外，有义和反义重复被翻译成毒性二肽重复（DPR）蛋白。尚不清楚这些重复序列如何翻译，以及它们的翻译和C9ORF72减少的表达如何调节重复毒性。在这里，我们发现有义和反义重复序列在标准AUG或近同源起始密码子上起始后即被翻译，产生了polyGA-，polyPG-和程度较低的polyGR-DPR蛋白。但是，自噬可防止这些蛋白质的积累。重要的是，降低的C9ORF72水平会导致自噬不足，从而损害DPR蛋白的清除并导致其毒性积累，最终导致神经元细胞死亡。具有临床重要性的激活自噬的药理化合物可以防止DPR蛋白积聚引起的神经元细胞死亡。这些结果表明，在ALS / FTD中存在双重打击的致病机制，因此C9ORF72的减少表达与DPR蛋白的积累和毒性协同作用。